Sustained release ranolazine formulations

ABSTRACT

A sustained release ranolazine formulation contains an intimate mixture of ranolazine and a partially neutralized pH-dependent binder to form a film that is mostly insoluble in aqueous media below pH 4.5 and soluble in aqueous media above pH 4.5. The formulation is suitable for twice daily administration of ranolazine and is useful for controlling the rate of dissolution of ranolazine, and to maintain human plasma ranolazine levels at between 550 and 7500 ng base/mL.

This is a continuation of co-pending U.S. patent application Ser. No.10/614,420 filed on Jul. 7, 2003, which is a continuation of U.S. patentapplication Ser. No. 10/259,143 filed Sep. 27, 2002 now U.S. Pat. No.6,617,328 which is a continuation of U.S. patent application Ser. No.10/041,521 filed Oct. 18, 2001 now U.S. Pat. No. 6,503,911 which is acontinuation of U.S. patent application Ser. No. 09/538,337 filed Mar.29, 2000 now U.S. Pat. No. 6,369,062 which is a continuation of U.S.Ser. No. 09/321,522 filed May 27, 1999 now U.S. Pat. No. 6,303,607 whichclaims priority to U.S. patent application Ser. No. 60/099,804 filedSep. 10, 1998, the specifications of each of which are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a method for using an orally administeredsustained release ranolazine dosage formulations to maintain humanranolazine plasma levels at therapeutic levels.

2. Description of the Art

U.S. Pat. No. 4,567,264, the specification of which is incorporatedherein by reference, discloses ranolazine,(±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide,and its pharmaceutically acceptable salts, and their use in thetreatment of cardiovascular diseases, including arrhythmias, variant andexercise-induced angina, and myocardial infarction.

U.S. Pat. No. 5,506,229, which is incorporated herein by reference,discloses the use of ranolazine and its pharmaceutically acceptablesalts and esters for the treatment of tissues experiencing a physical orchemical insult, including cardioplegia, hypoxic or reperfusion injuryto cardiac or skeletal muscle or brain tissue, and for use intransplants. Conventional oral and parenteral formulations aredisclosed, including controlled release formulations. In particular,Example 7D of U.S. Pat. No. 5,506,229 describes a controlled releaseformulation in capsule form comprising microspheres of ranolazine andmicrocrystalline cellulose coated with release controlling polymers.

The presently preferred route of administration for ranolazine and itspharmaceutically acceptable salts and esters is oral. A typical oraldosage form is a compressed tablet, a hard gelatin capsule filled with apowder mix or granulate, or a soft gelatin capsule (softgel) filled witha solution or suspension. U.S. Pat. No. 5,472,707, the specification ofwhich is incorporated herein by reference, discloses a high-dose oralformulation employing supercooled liquid ranolazine as a fill solutionfor a hard gelatin capsule or softgel.

As set forth in application Example 3, the initial trials of ranolazineon humans suffering from angina were failures. The trials used animmediate release of ranolazine formulation at a dose level of 120 mgtaken three times daily. Based upon the initial experiments, it wasuncertain whether or not ranolazine could be given to humans in anamount and mode that is effective against angina.

One problem with conventional oral dosage formulations is that they arenot ideally suited to ranolazine and its pharmaceutically acceptablesalts, because the solubility of ranolazine is relatively high at thelow pH that occurs in the stomach. Furthermore ranolazine also has arelatively short plasma half-life. The high acid solubility property ofranolazine results in rapid drug absorption and clearance, causing largeand undesirable fluctuations in plasma concentration of ranolazine and ashort duration of action, thus necessitating frequent oraladministration for adequate treatment.

There is therefore a need for a method for administering ranolazine inan oral dosage form once or twice daily that provides therapeuticallyeffective plasma concentrations of ranolazine for the treatment ofangina in humans.

SUMMARY OF THE INVENTION

In a first aspect, this invention is a sustained release ranolazineformulation where the majority of the formulation consists of activeranolazine.

In another aspect, this invention is a method of treating a humanpatient who is suffering from angina or other coronary disorders byadministering a sustained release ranolazine formulation to the patientonce or twice daily.

In yet another aspect, this invention is a method for treating a mammalhaving a disease state for which the administration of ranolazine isindicated, comprising the once or twice-daily administration ofsustained release ranolazine formulation of this invention in a mannerthat maintains plasma ranolazine close to minimal effective levelswithout peak fluctuations.

Still another aspect of this invention is a method of maintaining usefullevels of ranolazine in human plasma by administering a ranolazinecontaining dosage form only one or twice daily.

This invention includes methods for treating a human patient sufferingfrom a cardiovascular disease selected from arrhythmias, variant andexercise-induced angina, and myocardial infarction. The method includesadministering a sustained release pharmaceutical dosage form includingat least 50% by weight ranolazine in no more than two tablets per doseto the human patient to maintain ranolazine plasma levels in the humanpatient of from about 550 to about 7500 ng base/mL for at least 24 hourswherein the dose is administered at a frequency selected from once,twice and three times over 24 hours.

This invention further includes methods for treating a human patientsuffering from a cardiovascular disease selected from arrhythmias,variant and exercise-induced angina, and myocardial infarction. Themethod includes administering a sustained release pharmaceutical dosageform including from about 70 to about 80% by weight ranolazine in nomore than two tablets per dose to the human patient to maintainranolazine plasma levels in the human patient of from about 1000 toabout 3900 ng base/mL for at least 24 hours wherein the dose isadministered at a frequency selected from one and two times over 24hours.

This invention also includes pharmaceutical dosage forms comprising atleast about 50 wt % ranolazine and at least one pH dependent binder thatinhibits the release of ranolazine from the sustained release dosageform when the sustained release dosage form is subjected to an aqueousenvironment having a pH of the stomach and that promotes the release ofa therapeutic amount of ranolazine in an aqueous solution having a pHabove about 4.5.

DETAILED DESCRIPTION OF THE INVENTION

“Ranolazine” is the compound (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine-acetamide, or its enantiomers(R)-(+)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide,and(S)-(−)-N-2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamideand their pharmaceutically acceptable salts, and mixtures thereof.Unless otherwise stated the ranolazine plasma concentrations used in thespecification and examples refers to ranolazine free base.

“Optional” and “optionally” mean that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “optional pharmaceutical excipients” indicatesthat a formulation so described may or may not include pharmaceuticalexcipients other than those specifically stated to be present, and thatthe formulation so described includes instances in which the optionalexcipients are present and instances in which they are not.

“Treating” and “treatment” refer to any treatment of a disease in amammal, particularly a human, and include:

-   -   (i) preventing the disease from occurring in a subject which may        be predisposed to the disease but has not yet been diagnosed as        having it;    -   (ii) inhibiting the disease, i.e., arresting its development; or    -   (iii) relieving the disease, i.e., causing regression of the        disease.

“Immediate release” (“IR”) refers to formulations or dosage units thatrapidly dissolve in vitro and are intended to be completely dissolvedand absorbed in the stomach or upper gastrointestinal tract.Conventionally, such formulations release at least 90% of the activeingredient within 30 minutes of administration.

“Sustained release” (“SR”) refers to formulations or dosage units ofthis invention that are slowly and continuously dissolved and absorbedin the stomach and gastrointestinal tract over a period of about sixhours or more. Preferred sustained release formulations are thoseexhibiting plasma concentrations of ranolazine suitable for no more thantwice daily administration with two or less tablets per dosing asdescribed below.

Plasma ranolazine concentration is a mean concentration determined byanalyzing the concentration of ranolazine in as few as five to as manyas ten humans who are on the same dosing schedule. It is important thatthe ranolazine concentration is a mean value because of variances inranolazine concentrations in individuals that may be caused bydifferences in weight, metabolism, or disease states which may cause oneperson to metabolize ranolazine faster or slower than an average person.The plasma ranolazine levels are determined from drawn blood ontoheparin.

Definitions of other terms used in this application are:

-   -   ANOVA=analysis of variance    -   ATP=adenosine triphosphate    -   ECG=electrocardiographic    -   ETT=exercise treadmill test    -   PDH=pyruvate dehydrogenase    -   C_(max)=maximum concentration    -   C_(tough)=residual concentration at 8 hours post-dose for IR        formulations and 12 hours post-dose for SR formulations A-C of        Example 2.    -   tid=three times per day    -   bid=twice daily    -   C_(x)=concentration at time x    -   T_(max)=time to maximum concentration    -   AUC_(x)=area under the curve after x hours or time interval

Percentages given are percentages by weight, unless otherwise stated.This invention involves sustained release ranolazine dosage forms aswell as methods for administering sustained release ranolazine dosageforms of this invention to provide for therapeutic plasma levels ofranolazine.

The sustained release ranolazine formulations of this invention arepreferably in the form of a compressed tablet comprising an intimatemixture of ranolazine and a partially neutralized pH-dependent binderthat controls the rate of ranolazine dissolution in aqueous media acrossthe range of pH in the stomach (typically approximately 2) and in theintestine (typically approximately about 5.5).

To provide for a sustained release of ranolazine, one or morepH-dependent binders are chosen to control the dissolution profile ofthe ranolazine formulation so that the formulation releases ranolazineslowly and continuously as the formulation passed through the stomachand gastrointestinal tract. The dissolution control capacity of thepH-dependent binder(s) is particularly important in a sustained releaseranolazine formulation because a sustained release formulation thatcontains sufficient ranolazine for twice daily administration may causeuntoward side effects if the ranolazine is released too rapidly(“dose-dumping”).

Accordingly, the pH-dependent binders suitable for use in this inventionare those which inhibit rapid release of drug from a tablet during itsresidence in the stomach (where the pH is below about 4.5), and whichpromotes the release of a therapeutic amount of ranolazine from thedosage form in the lower gastrointestinal tract (where the pH isgenerally greater than about 4.5). Many materials known in thepharmaceutical art as “enteric” binders and coating agents have thedesired pH dissolution properties. These include phthalic acidderivatives such as the phthalic acid derivatives of vinyl polymers andcopolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates,hydroxyalkylcellulose acetates, cellulose ethers, alkylcelluloseacetates, and the partial esters thereof, and polymers and copolymers oflower alkyl acrylic acids and lower alkyl acrylates, and the partialesters thereof.

Preferred pH-dependent binder materials which can be used in conjunctionwith ranolazine to create a sustained release formulation aremethacrylic acid copolymers. Methacrylic acid copolymers are copolymersof methacrylic acid with neutral acrylate or methacrylate esters such asethyl acrylate or methyl methacrylate. A most preferred copolymer ismethacrylic acid copolymer, Type C, USP (which is a copolymer ofmethacrylic acid and ethyl acrylate having between 46.0% and 50.6%methacrylic acid units). Such a copolymer is commercially available,from Röhm Pharma as Eudragit® L 100-55 (as a powder) or L30D-55 (as a30% dispersion in water). Other pH-dependent binder materials which maybe used alone or in combination in a sustained release ranolazine dosageform include hydroxypropyl cellulose phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinylacetatephthalate, polyvinylpyrrolidone phthalate, and the like. One or morepH-dependent binders are present in the ranolazine dosage forms of thisinvention in an amount ranging from about 1 to about 20 wt %, morepreferably from about 5 to about 12 wt % and most preferably about 10 wt%.

One or more pH-independent binders may be in used in sustained releaseranolazine oral dosage forms. It is to be noted that pH-dependentbinders and viscosity enhancing agents such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like,do not themselves provide the required dissolution control provided bythe identified pH-dependent binders. The pH-independent binders arepresent in the formulation of this invention in an amount ranging fromabout 1 to about 10 wt %, and preferably in amount ranging from about 1to about 3 wt % and most preferably about 2.0 wt %.

As shown in Table 1, ranolazine is relatively insoluble in aqueoussolutions having a pH above about 6.5, while the solubility begins toincrease dramatically below about pH 6. TABLE 1 Solution pH Solubility(mg/mL) USP Solubility Class 4.81 161 Freely soluble 4.89 73.8 Soluble4.90 76.4 Soluble 5.04 49.4 Soluble 5.35 16.7 Sparingly soluble 5.825.48 Slightly soluble 6.46 1.63 Slightly soluble 6.73 0.83 Very slightlysoluble 7.08 0.39 Very slightly soluble 7.59 0.24 Very slightly soluble(unbuffered water) 7.73 0.17 Very slightly soluble 12.66 0.18 Veryslightly solubleIncreasing the pH-dependent binder content in the formulation decreasesthe release rate of ranolazine from the formulation at pH is below 4.5typical of the pH found in the stomach. The enteric coating formed bythe binder is less soluble and increases the relative release rate abovepH 4.5, where the solubility of ranolazine is lower. A proper selectionof the pH-dependent binder allows for a quicker release rate ofranolazine from the formulation above pH 4.5, while greatly affectingthe release rate at low pH. Partial neutralization of the binderfacilitates the conversion of the binder into a latex like film whichforms around the individual ranolazine granules. Accordingly, the typeand the quantity of the pH-dependent binder and amount of the partialneutralization composition are chosen to closely control the rate ofdissolution of the ranolazine from the formulation.

The dosage forms of this invention should have a quantity ofpH-dependent binders sufficient to produce a sustained releaseformulation from which the release rate of ranolazine is controlled suchthat at low pHs (below about 4.5) the rate of dissolution issignificantly slowed. In the case of methacrylic acid copolymer, type C,USP (Eudragit® L 100-55), a suitable quantity of pH-dependent binder isbetween 5% and 15%. The pH dependent binder will typically have fromabout 1 to about 20% of the binder methacrylic acid carboxyl groupsneutralized. However, it is preferred that the degree of neutralizationranges from about 3 to 6%.

The sustained release formulation may also contain pharmaceuticalexcipients intimately admixed with the ranolazine and the pH-dependentbinder. Pharmaceutically acceptable excipients may include, for example,pH-independent binders or film-forming agents such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g. the methylmethacrylate/ethyl acrylate copolymers sold under the trademarkEudragit® NE by Röhm Pharmal, starch, gelatin, sugars,carboxymethylcellulose, and the like. Other useful pharmaceuticalexcpients include diluents such as lactose, mannitol, dry starch,microcrystalline cellulose and the like; surface active agents such aspolyoxyethylene sorbitan esters, sorbitan esters and the like; andcoloring agents and flavoring agents. Lubricants (such as talc andmagnesium stearate) and other tableting aids are also optionallypresent.

The sustained release ranolazine formulations of this invention have aranolazine content of above about 50% by weight to about 95% or more byweight, more preferably between about 70% to about 90% by weight andmost preferably from about 70 to about 80% by weight; a pH-dependentbinder content of between 5% and 40%, preferably between 5% and 25%, andmore preferably between 5% and 15%; with the remainder of the dosageform comprising pH-independent binders, fillers, and other optionalexcipients.

Particularly preferred sustained release ranolazine formulations of thisinvention consist, essentially of: Weight Preferred Most IngredientRange (%) Range (%) Preferred (%) Ranolazine 50-95 70-90 75Microcrystalline cellulose  1-35  5-15 10.6 (filler) Methacrylic acidcopolymer  1-35   5-12.5 10.0 Sodium hydroxide 0.1-1.0 0.2-0.6 0.4Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0 Magnesium stearate 0.5-5.01-3 2.0

The sustained release ranolazine formulations of this invention areprepared as follows: ranolazine and pH-dependent binder and any optionalexcipients are intimately mixed (dry-blended). The dry-blended mixtureis then granulated in the presence of an aqueous solution of a strongbase which is sprayed into the blended powder. The granulate is dried,screened, mixed with optional lubricants (such as talc or magnesiumstearate), and compressed into tablets. Preferred aqueous solutions ofstrong bases are solutions of alkali metal hydroxides, such as sodium orpotassium hydroxide, preferably sodium hydroxide, in water (optionallycontaining up to 25% of water-miscible solvents such as lower alcohols).

The resulting ranolazine containing tablets may be coated with anoptional film-forming agent, for identification, taste-masking purposesand to improve ease of swallowing. The film forming agent will typicallybe present in an amount ranging from between 2% and 4% of the tabletweight. Suitable film-forming agents are well-known to the art andinclude hydroxypropyl methylcellulose, cationic methacrylate copolymers(dimethylaminoethyl methacrylate/methyl-butyl methacrylatecopolymers—Eudragit® E—Röhm Pharma), and the like. These film-formingagents may optionally contain colorants, plasticizers, and othersupplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of ranolazine in the tablet. The tablets will include from300 to 1100 mg of ranolazine free base. Preferably, the tablets willinclude amounts of ranolazine free base ranging from 400-600 mg, 650-850mg, and 900-1100 mg.

In order to influence the dissolution rate, the time during which theranolazine containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

Surprisingly, it has been found that these methods produce sustainedrelease ranolazine formulations that provide lower peak plasmaranolazine levels and yet effective plasma concentrations of ranolazinefor up to 12 hours and more after administration, when the ranolazineused as its free base, rather than as the more pharmaceutically commonranolazine dihydrochloride salt or as another salt or ester. The use ofranolazine free base affords at least one advantage: The proportion ofranolazine in the tablet can be increased, since the molecular weight ofranolazine free base is only 85% that of ranolazine dihydrochloride. Inthis manner, delivery of an effective amount of ranolazine is achievedwhile limiting the physical size of the dosage unit.

Another advantage of sustained release ranolazine formulations of thisinvention is that they are prepared by a process that essentiallyinvolves only water as a solvent, and utilizes standard pharmaceuticalprocessing techniques and equipment.

The sustained release ranolazine formulations of this invention can beused for treating cardiovascular diseases, including arrhythmias,variant and exercise-induced angina, and myocardial infarction;treatment of tissues experiencing a physical or chemical insult,including cardioplegia, hypoxic or reperfusion injury to cardiac orskeletal muscle or brain tissue, and ischemia; and peripheral arterialdiseases, such as intermittent claudication. It is most preferred thatthe sustained release dosage formulation be used as a mammaliananti-anginal agent and most preferably as a human anti-anginal agent.

The oral sustained release ranolazine dosage formulations of thisinvention are administered one, twice; or three times in a 24 hourperiod in order to maintain a plasma ranolazine level above thethreshold therapeutic level and below the maximally tolerated levels, ofbetween about 550 and 7500 ng base/mL in a patient. This corresponds toan amount of ranolazine 2 HCl ranging from about 644 ng/mL to about 8782ng/mL. Furthermore, the timing of the oral ingestion of the ranolazineoral dosage forms should be controlled to insure that the plasmaranolazine level does not exceed about 7500 ng base/mL and preferably sothat the plasma ranolazine level does not exceed about 5000 ng base/mLan most preferably so that is does not exceed 3800 ng base/mL. In someinstances it may be beneficial to limit the peak plasma ranolazine levelto no more than about ng base/mL At the same time, the plasma troughranolazine levels should preferably not fall below about 1000 ngbase/mL, and in some instances should not fall below 1700 ng base/mL

In order to achieve the preferred plasma ranolazine level of from about1000 to about 3800 ng base/mL, it is preferred that the oral ranolazinedosage forms described herein are administered once or twice daily. Ifthe dosage forms are administered twice daily, then it is preferred thatthe oral ranolazine dosage forms are administered at about twelve hourintervals.

In addition to formulating and administering oral sustained releasedosage forms of this invention in a manner that controls the plasmaranolazine levels, it is also important to minimize the differencebetween peak and trough plasma ranolazine levels. The peak plasmaranolazine levels are typically achieved at from about 30 minutes toeight hours or more after initially ingesting the dosage form whiletrough plasma ranolazine levels are achieve at about the time ofingestion of the next scheduled dosage form. It is preferred that thesustained release dosage forms of this invention are administered in amanner that allows for a peak ranolazine level no more than 8 timesgreater than the trough ranolazine level, preferably no more than 4times greater than the trough ranolazine and most preferably no greaterthan 2 times trough ranolazine level.

The sustained release ranolazine formulations of this invention providethe therapeutic advantage of minimizing variations in ranolazine plasmaconcentration while permitting, at most, twice-daily administration. Theformulation may be administered alone, or (at least initially) incombination with an immediate release formulation if rapid achievementof a therapeutically effective plasma concentration of ranolazine isdesired or by soluble IV formulations and oral dosage forms.

The following Examples are representative of the invention, but are notto be construed as limiting the scope of the claims.

EXAMPLES

These Examples detail methods for manufacturing ranolazine dosage formsas well as experiments performed to evaluate the effectiveness ofranolazine administration and effectiveness. Throughout these Examplesit should be noted that:

(1) Oral doses of the instant release (IR) formulation were given ascapsules or tablets of the dihydrochloride salt and are expressed as thedihydrochloride salt.

(2) Oral doses of the sustained release (SR) formulation were given astablets of the ranolazine base and are expressed as the base.

(3) When IR and SR formulations were compared in the same study, dosesare expressed in terms of both base and dihydrochloride. The conversionfactor for dihydrochloride to base is 0.854 (e.g.: 400 mgdihydrochloride×0.854=342 mg free base equivalent).

(4) All plasma levels and pharmacokinetic parameters are expressed aslevels of free base.

Example 1

This Example describes a method of preparing immediate release (IR)ranolazine formulations. Ranolazine dihydrochloride (4000 g),microcrystalline cellulose (650 g), polyvinylpyrrolidone (100 g), andcroscarmellose sodium (100 g) powders were intimately mixed together ina Fielder PMA 65 mixer-granulator, and sufficient water was then added,with mixing to form a granulate. The granulate was dried in an AeromaticStrea-5 fluid bed drier, screened, and mixed with magnesium stearate(100 g). The mixture was filled into hard gelatin capsules to a fillweight of, for example, 500 mg per capsule to achieve a dose of 400 mgof ranolazine dihydrochloride (equivalent to 342 mg of ranolazine freebase) per capsule, but may be filled to fill weight of 30 to 400 mg ofranolazine dihydrochloride.

Example 2

This Example describes a method of preparing sustained release (SR)ranolazine formulations.

A sustained release (SR) formulation, designated as SR Formulation A,and including pH-dependent and pH-independent binders was prepared bycombining Ranolazine (2500 g), methacrylic acid copolymer, Type C(Eudragit® L 100-55—Röhm Pharma) (1000 g), microcrystalline cellulose(Avicel®) (100 g) (710 g), and polyvinyl pyrrolidinone powders wereintimately mixed together in a Fielder PMA 65 mixer-granulator. Themixture was granulated with a solution of sodium hydroxide (40 g) inwater, and a 30% aqueous dispersion of methyl methacrylate/ethylacrylate copolymer (Eudragit® NE 30 D—Röhm Pharma) (1667 g) was added tothe wet mass. The resulting granulate was dried in an Aeromatic Strea-5fluid bed drier, screened, and then mixed with croscarmellose sodium(100 g) and magnesium stearate (50 g). The mixture was compressed into684 mg tablets with a Manesty B tablet press to achieve dose of 342 mgof ranolazine free base per tablet. This formulation is referred to asSR Formulation A.

SR Formulation B was prepared in the same manner as SR Formulation Aexcept that the Eudragit® L 100-55 was reduced to 500 g, and theEudragit® NE 30 D was replaced by a 40% aqueous dispersion of a methylmethacrylate/ethyl acrylate copolymer (Eudragit® NE 40 D—Röhm Pharma)(2500 g). The resulting (SR) formulation included 342 mg ranolazine freebase per tablet.

In SR Formulation C, ranolazine free base (342 mgs) was blended withmicrocrystalline cellulose and polyvinyl pyrrolininone K25, granulatedwith water, dried, and blended with croscarmellose sodium and magnesiumstearate. The blend was compressed into tablets and coated with anenteric coating.

SR Formulation D, including a pH dependent binder and a pH independentbinder was prepared by combining Ranolazine (7500 g), Eudragit® L 100-55(1000 g), hydroxypropyl methylcellulose (Methocel® E5—source) (200 g),and microcrysalline cellulose (Avicel®) (1060 g) by intimate mixing. Themixed powders were granulated with a solution of sodium hydroxide (40 g)in water (1900 to 2500 grams). The granulate was dried and screened,mixed with magnesium stearate (200 g), and compressed for example intotablets weighing 667 mg to achieve a dose of 500 mg of ranolazine freebase per tablet. The tablets were spray coated in a 24 inch Accelacota®cylindrical pan coater with OPADRY film coating solution to a 2-4%weight gain. OPADRY film coating solutions are available in a variety ofcolors from Colorcon, West Point, Pa.

The stepwise procedure for preparing SR Formulation D is as follows:

-   -   a) Blend together ranolazine, microcrystalline cellulose,        methacrylate copolymer (Type C) and hydroxypropyl methyl        cellulose using an appropriate blender.    -   b) Dissolve sodium hydroxide in purified water.    -   c) Using appropriate granulation equipment, slowly add the        sodium hydroxide solution to the blend with constant mixing. Add        a further aliquot of water, if necessary.    -   d) Continue mixing to achieve additional massing. Add a further        aliquot of water, if necessary.    -   e) Dry granulated in a fluid bed dryer.    -   f) Screen dried granules through an appropriate mill.    -   g) Add magnesium stearate to the screened granules and blend        together.    -   h) Pass the granulated material through a chilsonator, if        needed.    -   i) Compress the granules into tablets using appropriately sized        tooling.    -   j) Disperse OPADRY powder in water and film-coat using        appropriately sized coating equipment to a typical level of 2-4%        by weight.    -   k) Polish with carnauba wax using a typical level of        0.002-0.003% by weight.

Example 3

This Example summarizes a study published in Circulation 90:726-734(1994) that demonstrated that ranolazine was ineffective as anantianginal and anti-ischemic agent when administered as an IRformulation of Example 1.

Patients with stable angina pectoris took part in the study. Anyprevious antianginal drugs used by the patients were discontinued undermedical supervision. Three hundred nineteen patients receivedsingle-blind placebo for up to 18 days, and 318 stopped exercise becauseof angina of moderate severity, had evidence of myocardial ischemia(≧1-mm ST segment depression), and were randomized to one of four studygroups and administered; ranolazine .2HCl 30 mg tid (n=81); ranolazine.2HCl 60 mg tid (n=81); ranolazine .2HCl 120 mg tid (n=78); and placebotid (n=79). After administration of 30-, 60- and 120-mg doses tid, themean peak plasma concentrations of ranolazine free base at 1 hour afterdose were 94, 219 and 510 ng/mL, respectively, and the mean troughplasma concentrations at 8 hours after dose were 18, 37 and 90 ng/mL,respectively.

After the 4-week double-blind phase, symptom-limited exercise tests wererepeated at 1 hour (peak test) and 8 hours (trough test) after the studymedication was administered. Total exercise duration at baseline (±SEM)was 5.9±0.2 minutes for the placebo group and 6.4±0.3, 5.9±0.3, and6.6±0.2 minutes for the ranolazine 30-, 60-, and 120-mg groups,respectively (P═NS). After 4 weeks of double-blind therapy, comparedwith baseline values, at 1 hour after the study medication wasadministered (peak effect), total exercise duration (±SEM) increased by0.45±0.2 minutes in the placebo group and by 0.3±0.2, 0.6±0.2, and0.5±0.2 minutes in the ranolazine 30-, 60- and 120-mg groups,respectively (placebo versus ranolazine, P═NS). Times to 1-mm ST-segmentdepression at baseline were similar in the four groups and, after 4weeks of therapy in each group, increased significantly by similarmagnitudes at 1 hour after the administration of the medications.Similar changes were seen for the time to onset of angina. Eight hoursafter administration (trough effect), no differences in total exercisetime or any other exercise variables were observed between the placeboand the ranolazine groups. Compared with the baseline values, the numberof anginal attacks per week and the number and duration of ischemicepisodes per 48 hours during Holter monitoring decreased significantlyby similar magnitudes in the placebo and ranolazine groups.

These results indicated that therapy with ranolazine .2HCl 30, 60 and120 mg tid was not superior to placebo. The study also did not showbeneficial effects of similar doses of ranolazine on either mycocardialischema or exercise performance or on anginal attacks during daily lifein patients with angina pectoris.

Example 4

In this Example, the safety and anti-ischemic effects of high plasmaranolazine levels in a large group of angina patients was evaluated andthe duration of any effects during steady-state dosing with bid and tidregimens was assessed. In this Example, patients with chronic stableangina pectoris who were responsive to conventional antianginal drugswere treated with 3 ranolazine .2HCl dosing regimens: 267 mg tid, 400 mgbid and 400 mg tid IR Formulations of Example 1. Exercise testingparameters and ranolazine free base concentrations were determined atpeak and trough plasma levels.

Methods

The study involved double-blind, placebo-controlled randomized treatmentphase with 4 treatments (placebo, ranolazine .2HCl 400 mg bid,ranolazine .2HCl 267 mg tid, and ranolazine .2HCl 400 mg tid), 4treatment sequences and 5 double-blind treatment periods in an extendedperiod Latin square design on pre-qualified patients who were responsiveto known antianginal therapy and had stable exercise times.

Human patients with chronic stable angina pectoris, of at least 3months' duration, that had responded to conventional antianginal therapywere considered candidates. In addition, patients had to haveelectrocardiogrpahic (ECG) evidence of exercise-induced ischemia basedupon horizontal or down-sloping ST-segment depression of ≧1 mm thatpersisted in 3 consecutive beats during an exercise stress test and anECG pattern that would not interfere with interpretation of ST-segmentchanges. The latter criterion specifically excluded patients with leftventricular hypertrophy, pre-excitation, conduction abnormalities, orpacemaker rhythm. Other exclusion criteria included unstable angina ormyocardial infarction within the preceding 3 months, heart failuredefined as New York Heart Association Class III or IV, significantvalvular or congenital heart disease that was uncorrected, need fordigoxin or long-acting nitrate therapy, labile diabetes mellitus, orother serious conditions that would confuse follow-up evaluation.

These immediate release ranolazine .2HCl dosing regimens (267 mg tid,400 mg bid, 400 mg tid) and a placebo were administered during thetreatment phase. Patients took one capsule containing either 267 mg or400 mg of ranolazine dihydrochloride, or placebo at 8:00 a.m., 4:00p.m., 8:00 p.m. and 12:00 a.m. All capsules were identical inappearance. Patients were randomized to 1 of 4 treatment sequences, with25% of the patients assigned to each sequence. Each treatment wasadministered for 1 week, with one treatment repeated during a fifth1-week period.

To qualify patients receiving their usual antianginal medicationsunderwent a screening exercise treadmill test (ETT-1) using a Sheffieldmodified Bruce protocol. If the time to onset angina was ≧3 but ≧13minutes, an antianginal drug was withdrawn and treatment withsingle-blind placebo was initiated. After 1 to 2 weeks, patientsreturned for another ETT (ETT-2). If the time to onset angina decreasedby 1 minute compared with ETT-1, the patient was considered to havecompleted the first qualifying ETT. If the decrease in time to onsetangina was not ≧1 minute, a second antianginal drug could be withdrawnand the above sequence repeated. If necessary, a third antianginal drugcould be withdrawn according to this procedure in order for the patientto qualify. Long-acting nitrates were always withdrawn first;beta-blockers; and calcium antagonists could be, withdrawn in eitherorder from patients not receiving long-acting nitrates. After thepatient achieved the first qualifying ETT (ETT-2), a second qualifyingETT (ETT-3) was performed in which the time to onset angina had to bewithin ±15% of that observed during ETT-2. In addition, each of thequalifying ETTs had to have ECG signs of ischemia (≧1 mm horizontal ordown-sloping ST-segment depression in 3 consecutive beats). Patientsmeeting these criteria were used in the study.

After each 1 week period, patients returned to the exercise laboratoryin the morning, at least 1 hour after a light breakfast, for an ETT.This was designated the trough ETT; the trough ETTs were performed atthe same time of day for each patient. After completing the trough ETT,the patient received the next scheduled blinded medication dose from theblister pack used that week. Another ETT was performed 1 hour after theadministered dose. This was designated the peak ETT. Blood samples wereobtained at trough (approximately 8 hours after dosing) and at peak (1hour after dosing). Other standard laboratory tests were monitoredregularly throughout the study.

Blood pressure (by cuff) and heart rate were monitored before all ETTs,during the ETT, during the last minute of each stage of the test, atonset angina, at the point of maximum exercise, and during recovery(every minute for 4 minutes, then every 5 minutes until values returnedto baseline). Heart rates also was monitored continuously and standard12-lead ECG recordings were done immediately before exercise with thepatient standing on the treadmill, at the end of each stage of exercise,at the maximally tolerated exercise load, and at the termination ofexercise.

Mean treadmill exercise times for the 3 exercise variables of interestduring placebo and the different ranolazine dosing regimens(ranolazine-placebo) for all patients at peak and trough are summarizedin Table 2 below. TABLE 2 Exercise Test Data for All Patients at Peakand Trough Mean Treatment Exercise Ranola- Ranola- Ranola- Variable (allDouble- zine zine zine patients, blind 400 267 400 minutes) Placebo mgbid mg tid mg tid Time to Peak 9.01 9.33 9.40 9.33 onset angina Trough8.58 8.77 8.78 8.65 Exercise Peak 10.67 10.83 10.87 10.84 DurationTrough 10.50 10.55 10.56 10.60 Time to 1 Peak 9.58 9.86 9.99 9.94 mm STTrough 9.04 9.22 9.22 9.31 depression

At peak ranolazine plasma concentrations, all ETT ischemia parameterswere prolonged over placebo and most notably, the time to onset of 1-mmST-segment depression. In the all-patients analysis, the increase intime to onset angina over placebo ranged from 0.32 to 0.39 minutes(p≦0.01) and time to onset of 1-mm ST-segment depression ranged from0.28 to 0.41 minutes (p≦0.02) for each of the 3 ranolazine dosingregimens and all regimens combined. Also, the total duration of exercisewas significantly increased for all regimens combined and trends ofsimilar direction and magnitude were noted for each dosing regimen. Inthe per-protocol analysis each of the 3 ETT parameters were prolonged(p≦0.01) for all ranolazine dosing regimens combined. All individualranolazine dosing regimens significantly prolonged time to 1-mmST-segment depression and nonsignificant trends of similar direction andproportions were found for time to onset angina and duration ofexercise. In general, results of the per-protocol analysis, except thatthe magnitude of the effect appeared to somewhat greater in those withmonotherapy.

At trough plasma concentrations, ranolazine had a lesser effect on ETTparameters. The results for the all-patients and per-protocol analyseswere relatively consistent, demonstrating trends to increased exercisetimes. But only the time to 1 mm ST-segment depression for allranolazine regimens combined in the all-patients analysis achievedstatistical significance.

In view of the more pronounced increases in exercise parameters observedwith ranolazine monotherapy, the responses to ranolazine among patientsreceiving different concomitant antianginal medications were analyzed.These post-hoc analyses were performed on peak ranolazine data, when theeffects to improve exercise times were most evident. Because long-actingnitrates were withdrawn first during the single-billed qualifying phase,no patient entered double-blind treatment receiving long-actingnitrates. Of patients with peak efficacy data, 34% (107/312) of thepatients received beta-blockers during double-blind treatment and 24%(75/312) received calcium antagonists.

Exercise test parameters improved at peak ranolazine concentrations(ranolazine-placebo) whether or not patients were receivingbeta-blockers. These improvements were slightly larger in magnitude inthe 205 patients not receiving beta-blockers compared to the 107patients who received beta-blockers. But the differences between thosereceiving beta-blockers and those not receiving them did not achievestatistical significance for any exercise parameter. In patients notreceiving beta-blockers, all exercise parameters improved significantlyon each of the 3 ranolazine regimens, and also with all ranolazineregimens combined. Similar trends were observed in the smaller number ofpatients receiving beta-blockers. Analyses of exercise data frompatients taking calcium antagonists compared with those not receivingcalcium antagonists produced similar findings.

Table 3 below summarizes the mean peak and trough plasma ranolazineconcentrations, in terms of ranolazine dihydrochloride base, for allpatients by gender and for each dosing regimen. TABLE 3 Mean (±StandardDeviation) Ranolazine Plasma Concentrations by Dosing Regimen RanolazineRanolazine Ranolazine 400 mg 267 mg 400 mg bid tid tid Peak (ng/mL) AllPatients 1882 (1094) 1346 (823)  2128 (1198) Males 1762 (999)  1261(774)  1917 (1046) Females 2171 (1253) 1594 (904)  2654 (1385) Trough(ng/mL) All Patients 235 (288) 316 (336) 514 (500) Males 235 (264) 316(336) 518 (494) Females 235 (342) 316 (340) 505 (517)The plasma mean peak concentrations ranged from 1346 to 2128 ng per mLranolazine free base. The 400 mg tid dosing regimen was associated withthe highest ranolazine plasma concentrations. Mean trough ranolazineplasma concentrations ranged from 235 to 514 ng per mL. Mean peakranolazine plasma concentrations were somewhat higher in females than inmales, but there were no sex differences in plasma concentrationsevident in trough.

At peak ranolazine plasma concentrations, there were no statisticallysignificant differences among any of the ranolazine dosing regimens andplacebo for double product. Likewise, at trough ranolazine plasmaconcentrations, there were no statistically significant differencesamong the 3 ranolazine dosing regimens and placebo in the per-protocolanalysis for standing or maximum exercise double product.

The results of this study suggest that ranolazine is an effectiveantianginal and anti-ischemic compound in patients with chronic stableangina pectoris. At peak plasma concentrations, the three ranolazinedosing regimens used prolonged time to onset of angina and duration ofexercise as well as time to 1-mm ST-segment depression on average about0.33 minutes over that observed with placebo. Improvement in exerciseparameters was observed in the present study not only in patientsreceiving concomitant antianginal therapy (eg, beta-blockers and calciumantagonists), but also in the subgroup who received only ranolazinemonotherapy. In the latter patients, the treatment effect appeared to besomewhat greater in magnitude. This suggests that ranolazine also may beuseful in monotherapy in patients with chronic stable angina pectoris.

The hemodynamic findings indicate that the improvement in exerciseparameters in peak ranolazine plasma concentrations was not associatedwith changes in blood pressure or heart rate. The nonhemodynamicmechanism of action of ranolazine, therefore, differs from that of otherantianginal drugs in current clinical use.

Most important, we documented that the antianginal and anti-ischemiceffects of the immediate-release ranolazine preparation studied did notpersist throughout the dosing interval. Although time to onset ofischemic-type ST-segment depression was significantly prolonged andtrends of similar direction were noted for other ETT parameters, theeffect was minimal at trough ranolazine plasma concentrations. Mean peakranolazine free base plasma concentrations ranged from 1346 to 2128 ngper mL, while mean trough plasma concentrations ranged from 235 to 514ng per mL. It seems evident that the higher mean ranolazine plasmaconcentrations observed at peak are associated with clinicallymeaningful antianginal and anti-ischemic effects, whereas concentrationsobtained at trough were not.

Based on the results of the present experiment, the threshold plasmaranolazine free base concentration for anti-ischemic activity detectedduring ETT is likely to lie above about 550 ng per mL. Further, it islikely that ranolazine plasma concentrations must be maintained at orabove the threshold value throughout the dosing interval to ensureantianginal and anti-ischemic activity during exercise throughout thisinterval.

Ranolazine was well tolerated over the plasma concentrations achieved inthe present study. The rate of occurrence of adverse events did notdiffer among the ranolazine dosing regimens and placebo, and there wereno drug-related changes in ECG intervals or complex morphology. Inaddition, there were no clinically significant changes in blood glucoseconcentrations, lipid values or liver function tests, suggesting thatthe metabolic effect of ranolazine does not extend to systemic glucoseregulation or lipid metabolism.

Ranolazine improves exercise parameters with no detectable effect onheart rate and blood pressure in patients with chronic stable anginapectoris. It is likely that a threshold ranolazine plasma concentrationabove about 550 ng per mL must be obtained to detect these antianginaland anti-ischemic effects. Ranolazine is well tolerated over a widerange of plasma concentrations. Further study using larger doses of asustained release preparation are warranted to fully evaluate this novelmetabolic concept for management of ischemia.

Example 5

I. In Vitro Comparison of IR Formulation and SR Formulations

The IR Formulation prepared according to Example 1 and the SRFormulations prepared according to Examples 2A-2C were tested in a USPApparatus 2 dissolution tester, using 900 mL of 0.1M hydrochloric acidas the dissolution fluid to simulate dissolution in the stomach. TABLE 4Percentage of Formulation Dissolved Time Formulation (hours) IR A B C0.25 88.1 0.5 100.5 13.9 17.6 17.5 1 101.7 19.9 26.0 25.7 2 27.8 47.535.9 4 39.0 69.2 48.4 8 52.4 90.1 64.7 12 61.6 99.6 74.2 24 80.8 105.695.4

The tabular results show that while the IR Formulation is completelydissolved in no more than 0.5 hours (as expected for an immediaterelease formulation), SR Formulations A, B, and C displayed a prolongeddissolution of a low pH, as is desirable for a sustained releaseformulation.

II. In Vivo Comparison of IR Formulation and SR Formulations A, B, and C

Single doses of the IR Formulation prepared according to Example 1 andSR Formulations A and B prepared according to Example 2 wereadministered to eleven healthy volunteers and their plasmaconcentrations of ranolazine free base were measured at 0, 20, 40, 60,90, and 120 minutes, hourly to six hours, twice-hourly to eighteenhours, and at twenty-four hours after administration (SR Formulationsonly). The results are set forth in Table 5 below. TABLE 5 FormulationIR A B C C_(max) (ISD) (ng/mL) 1940 (807) 753 (264) 657 (316) 925 (747)C_(trough)(ISD)(ng/mL) 165 (111) 158 (114) 182 (110) 290 (163) T_(max)(ISD) (hours) 1.27 (0.5) 4.09 (1.14) 4.05 (1.31) 6.55 (2.93) AUC₀₋₂₄(ISD) (ng · hr/mL) 6530 5640 5280 5820

From Table 5 it is apparent that SR Formulations A, B and C of thisinvention exhibit dissolution properties which make them suitable fortwice daily administration of ranolazine.

Example 6

This Example details a single-ascending dose, crossover-design studythat assessed the safety and pharmacokinetic profile of single oral doseof ranolazine base SR Formulation of Example 2D. Human subjects weredivided into three groups. Group 1 received 500, 750 and 1000 mgranolazine SR. Group 2 received 1250 and 1750 mg ranolazine SR. Group 3received 1500 and 2000 mg ranolazine SR. Each group also had arandomized placebo phase. Mean pharmacokinetic parameters followingsingle oral doses of the ranolazine SR does are detailed in Table 6below: TABLE 6 Mean ± SD Pharmacokinetic Parameters (n = 8 except* n =7) C_(max) C_(trough) AUC_(0-30rh) Dose SR (mg) Group (ng/mL) (ng/mL)T_(max) (hr) (ng · hr/mL) 500 1 883 ± 353 382 ± 251 4.63 ± 1.19 9380 ±4250 750 1 1300 ± 1060 455 ± 353  4.25 ± 0.886 12500 ± 9000  1000  1*1610 ± 959  695 ± 438 5.71 ± 2.14 18100 ± 9630  1250 2 2210 ± 716  943 ±541 6.21 ± 3.52 25000 ± 8090  1500 3 1980 ± 1050 1070 ± 754   4.75 ±0.886 25400 ± 16000 1750 2 3670 ± 1570 2400 ± 1260 5.25 ± 2.31 49200 ±18200 2000 3 2440 ± 1120 1640 ± 937  5.21 ± 2.30 35400 ± 19100The pharmacokinetic results reported in Table 6 indicate that ranolazinewas slowly released from the SR formulation, and consequently theabsorption of ranolazine was dissolution-rate limited. This resulted inprolonged plasma drug concentration-time profiles observed at all doselevels, with peak plasma levels at 4 to 6 hours post dose. Over the doserange 500 to 2000 mg, the mean C_(max) and AUC₀ ₋ _(30 hr) increased inan approximately dose-proportional manner, although there appeared to besome deviation from portionality within Group 2.

Example 7

This Example details a double-blind, placebo-controlled, multipleascending-dose, crossover-designed volunteer study, to evaluate biddosing. Six subjects received 4 days dosing with ranolazine SRformulation prepared according to Example 2D at 500, 750, and 1000 mgbid, followed by a morning dose on Day 5. Pharmacokinetic results arereported in Table 7, below. TABLE 7 Day 5 Ranolazine PharmacokineticParameters (mean ± SD) Ranolazine SR Ranolazine SR Ranolazine SR 500 mgbid 750 mg bid 1000 mg bid Parameter (n = 7) (n = 7) (n = 7) C_(max)(ng/mL) 1760 ± 715  2710 ± 657  3660 ± 1090 T_(max) (hr) 2.00 ± 1.154.33 ± 1.62 4.17 ± 2.48 C_(min) (ng/mL) 585 ± 340 1260 ± 501  1960 ±812 

According to Table 7, ranolazine was slowly released from the SRformulation, and consequently the pharmacokinetics were dissolution-ratelimited. This resulted in extended plasma drug concentration-timeprofiles at all dose levels, with peak plasma levels observed at 2 to 4hours post dose.

These results indicate that useful ranolazine plasma levels can beachieved in humans with dosing of this SR formulation on a bid schedule.

Example 8

This Example evaluated the safety and tolerability of administeringracemic ranolazine free base formulations as in Example 2D. Theindividual and mean concentrations of racemic ranolazine and itsenantiomers,(R)-(+)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide,(S)-(−)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamidein human plasma were also determined.

The study was performed with ascending doses of sustained releaseranolazine dosage forms. Before and at intervals during and after thedosing period, blood samples were drawn for ranolazine assay and bloodpressure, heart rate, ECG and symptoms were monitored throughout. Datasummaries were reviewed after each phase before proceeding to the nextphase of the study.

Eight subjects, all healthy male volunteers aged between 18 and 40entered and all completed the study and were available forpharmacokinetic and safety analysis. The subjects were each given dosesof the various types of ranolazine free base in the form of sustainedrelease tablets including 500 mg and 750 mg tablets or with matchingplacebo as necessary (2×750 mg size plus 1×500 mg size) to make unitoral doses of 1500 and 2000 mg.

In each phase: one dose bid for four days with a single dose on Day 5.On day 5 each volunteer underwent a full pharmacokinetic profileincluding supine and erect blood pressure (BP) and heart rate, ECG data,adverse events, clinical chemistry and hematology results, urinalysisresults.

Steady state was tested for in each dose level, using C_(48 h), C_(72 h)and C_(96 h) and log transformed data, by analysis of covariance and bytesting whether the coefficient for time was significantly different(defined as p<0.05) from 0. These tests were made using two-sidedt-tests with estimates of variability from the ANOVA models. Steadystate was also assessed by comparing means for C_(48 h), C_(72 h) andC_(96 h) using a mixed effects ANOVA model and untransformed and log,transformed data. For hemodynamic parameters, Day 1 pre-dose treatmentmeans and Day 5 data were compared across treatments via two-sidedt-tests using estimates of variability from mixed effects ANOVA models.Ninety and 95% confidence intervals were calculated for the treatmentcomparisons. No adjustments were made for multiple comparisons.

The mean and standard deviation day 5 pharmacokinetic parameters ofranolazine free base are detailed in Table 8 below and the mean plasmaprofiles are shown in the figure. Steady-state plasma levels ofranolazine free base appeared to be attained by day 4. Within the doseinterval there was a slow rise to maximum levels with t_(max) valuesranging from 1 to 6 h post-dose. Thereafter levels declined slowly,producing a small degree of fluctuation in plasma levels over the dosinginterval. There appeared to be no differences in the pharmacokineticparameters of the (+) R and (−) S enantiomers of ranolazine followingmultiple dosing with this SR formulation. TABLE 8 Day 5 Racemic (RS),(+)R and (−)S Ranolazine SR Pharmacokinetic Parameters 1500 mg SR bid2000 mg SR bid Parameter RS ranolazine (+)R ranolazine (−)S ranolazineRS ranolazine C_(max) (ng/ml) 5284 ± 2434 2909 ± 1308 2944 ± 1426 7281 ±2700 C_(min) (ng/ml) 2932 ± 1918 1436 ± 1046 1514 ± 1201 4149 ± 2228Median t_(max) (h) 4.00 4.00 4.00 4.00 C_(96 h) (ng/ml) 3656 ± 1918 2009± 1137 2399 ± 1205 5042 ± 1797 C_(108 h) (ng/ml) 2942 ± 1937 1447 ± 10711541 ± 1260 4398 ± 2396 AUC_(96-108 h) (ng · h/ml) 49516 ± 23945 25731 ±13385 26407 ± 14849 68459 ± 25842 C_(ave) (ng/ml) 4126 ± 1995 2144 ±1115 2201 ± 1237 5705 ± 2153 Degree of fluctuation 0.664 ± 0.336 0.833 ±0.402 0.824 ± 0.443 0.591 ± 0.240

Some subjects became too symptomatic on standing to complete BPmeasurements on ranolazine 1500 mg (n=3 of 8) and 2000 mg (n=2 of 8),usually 2-6 hours post-dose. Statistically significant reductions inorthostatic systolic BP were noted on day 5 on 1500 mg (−9.8 mm Hg; 4hours post-dose) and 2000 mg (−8.4 mmHg; 6 hours post-dose). Althoughthe pattern of adverse events was similar on ranolazine and placebo,headache, dizziness and blocked nose seemed more common on ranolazine.

1. A method for treating a human patient suffering from a cardiovasculardisease selected from arrhythmias, variant and exercise-induced angina,and myocardial infarction by administering a sustained releasepharmaceutical dosage form including at least 50% by weight ranolazinein no more than two tablets per dose to the human patient to maintainranolazine plasma levels in the human patient of from about 550 to about7500 ng base/mL for at least 24 hours wherein the dose is administeredat a frequency selected from once, twice and three times over 24 hours.2. The method of claim 1 wherein the sustained release dosage formincludes at least one pH dependent binder wherein the pH dependentbinder inhibits the release of ranolazine from the sustained releasedosage form when the sustained release dosage form is subjected to anaqueous environment having a pH of the stomach and wherein the pHdependent binder promotes the release of a therapeutic amount ofranolazine in an aqueous solution having a pH above about 4.5.
 3. Themethod of claim 2 wherein the pH dependent binder is partiallyneutralized.
 4. The method of claim 1 wherein the pharmaceutical dosageform is administered to the human patient at a frequency selected fromonce and twice over 24 hours.
 5. The method of claim 1 wherein thepharmaceutical dosage form is administered to the human patient in twodosed over 24 hours wherein each dose consists of two tablets.
 6. Themethod of claim 1 wherein the pharmaceutical dosage form includesbetween about 50% to about 950% by weight ranolazine.
 7. The method ofclaim 1 wherein the pharmaceutical dosage form includes from about 70%to about 80% by weight ranolazine.
 8. The method of claim 2 wherein thepH dependent binder is selected from methacrylic acid copolymers,hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulosephthalate, cellulose acetate phthalate, polyvinyl acetate, phthalate,polyvinylpyrrolidine phthalate, and mixtures thereof.
 9. The method ofclaim 2 wherein the pH dependent binder is a methacrylic acid copolymer.10. The method of claim 9 wherein the methacrylic acid copolymer ismethacrylic acid copolymer Type C USP.
 11. The method of claim 2 whereinthe pH dependent binder is from about 5 to about 12 wt % methacrylicacid copolymer Type C USP.
 12. The method of claim 1 wherein the pHdependent binder is about 10 wt % methacrylic acid copolymer Type C USP.13. The method of claim 1 wherein the pharmaceutical dosage formincludes a pH-independent binder.
 14. The method of claim 13 wherein thepH-independent binder is selected from hydroxypropyl methylcellulose,hydroxypropyl cellulose, poly(meth)acrylate esters,poly-vinylpyrrolidone, and mixtures thereof.
 15. The method of claim 13wherein the pH-independent binder is hydroxypropyl methylcellulose. 16.The method of claim 15 wherein the pharmaceutical dosage form includesfrom about 1 to about 3 wt % hydroxypropyl methylcellulose.
 17. Themethod of claim 15 wherein the pharmaceutical dosage form includes about2 wt % hydroxypropyl methylcellulose.
 18. The method of claim 1 or 6 or7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein thehuman patient plasma ranolazine level ranges from 1000-5000 ng base/mL.19. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or14 or 15 or 16 or 17 wherein the human patient plasma ranolazine levelranges from 1000-3800 ng base/mL.
 20. The method of claim 1 or 6 or 7 or8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the humanpatient plasma ranolazine level ranges from 550-5000 ng base/mL.
 21. Themethod of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or15 or 16 or 17 wherein the human patient plasma ranolazine level rangesfrom 550-3800 ng base/mL.
 22. The method of claim 1 or 6 or 7 or 8 or 9or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the humanpatient plasma ranolazine level ranges from 1000-2800 ng base/mL. 23.The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14or 15 or 16 or 17 wherein the human patient plasma ranolazine levelranges from 1700-3900 ng base/mL.
 24. The method of claim 1 or 6 or 7 or8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the humanpatient plasma ranolazine level ranges from 550-2000 ng base/mL.
 25. Themethod of claim 23 wherein the dosage form includes from 650-850 mgranolazine.
 26. The method of claim 24 wherein the dosage form includesfrom 900-1100 mg ranolazine.
 27. The method of claim 25 wherein thedosage form includes from 400-600 mg ranolazine.
 28. The method of claim22 or 23 or 24 or 25 or 26 or 27 wherein the peak to trough humanpatient plasma ranolazine levels is less than 4:1 over a 24 hour period.29. The method of claim 23 or 24 or 25 or 26 or 27 wherein the peak totrough human patient plasma ranolazine levels is less than 3:1 over a 24hour period.
 30. The method of claim 24 or 28 wherein the peak to troughhuman patient plasma ranolazine levels is less than 2:1 over a 24 hourperiod.
 31. A pharmaceutical dosage form comprising at least about 50 wt% ranolazine and at least one pH dependent binder that inhibits therelease of ranolazine from the sustained release dosage form when thesustained release dosage form is subjected to an aqueous environmenthaving a pH of the stomach and that promotes the release of atherapeutic amount of ranolazine in an aqueous solution having a pHabove about 4.5.
 32. The pharmaceutical dosage form of claim 31including no more than two tablets per dose.
 33. The pharmaceuticaldosage form of claim 32 wherein the pharmaceutical dosage form includesfrom about 50% to about 95% by weight ranolazine.
 34. The pharmaceuticaldosage form of claim 32 wherein the pharmaceutical dosage form includesfrom about 70% to about 80% by weight ranolazine.
 35. The pharmaceuticaldosage form of claim 31 wherein the pH dependent binder is selected frommethacrylic acid copolymers, hydroxypropyl cellulose phthalate,hydroxypropyl methycellulose phthalate, cellulose acetate phthalate,polyvinyl acetate, phthalate, polyvinylpyrrolidine phthalate, andmixtures thereof
 36. The pharmaceutical dosage form of claim 31 whereinthe pH dependent binder is a methacrylic acid copolymer.
 37. Thepharmaceutical dosage form of claim 36 wherein the methacrylic acidcopolymer is methacrylic acid copolymer Type C USP.
 38. Thepharmaceutical dosage form of claim 36 wherein pharmaceutical dosageform includes from about 5 to about 12 wt % methacrylic acid copolymerType C USP.
 39. The pharmaceutical dosage form of claim 36 wherein thepharmaceutical dosage form includes about 10 wt % methacrylic acidcopolymer.
 40. The pharmaceutical dosage form of claim 31 wherein thepharmaceutical dosage form includes a pH-independent binder.
 41. Thepharmaceutical dosage form of claim 40 wherein the pH-independent binderis selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose,poly(meth)acrylate esters, poly-vinylpyrrolidone, and mixtures thereof.42. The pharmaceutical dosage form of claim 40 wherein thepH-independent binder is hydroxypropyl methylcellulose.
 43. Thepharmaceutical dosage form of claim 42 wherein the pharmaceutical dosageform includes from about 1 to about 3 wt % hydroxypropylmethylcellulose.
 44. The pharmaceutical dosage form of claim 42 whereinthe pharmaceutical dosage form includes about 2 wt % hydroxypropylmethylcellulose.
 45. The pharmaceutical dosage form of claim 31 whereinthe dosage form includes from about 650 to about 850 mg ranolazine. 46.The pharmaceutical dosage form of claim 31 wherein the dosage formincludes from about 900 to about 1100 mg ranolazine.
 47. Thepharmaceutical dosage form of claim 31 wherein the dosage form includesfrom about 400 to about 600 mg ranolazine.
 48. The pharmaceutical dosageform of claim 31 wherein the dosage form includes from about 300 toabout 1000 mg ranolazine.
 49. The pharmaceutical dosage form of claim 32wherein the pharmaceutical dosage form is a compressed tablet.
 50. Acompressed tablet comprising from about 70 to about 80 wt % ranolazine,at least one pH dependent binder selected from methacrylic acidcopolymers, hydroxypropyl cellulose phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinylacetate, phthalate, polyvinylpyrrolidine phthalate, and mixturesthereof, and at least one pH independent binder wherein the compressedtablet includes from about 350 to about 800 mg ranolazine.